The body's inflammatory response to tissue injury can cause significant tissue destruction, leading to loss of tissue function. Damage to cells resulting from the effects of inflammatory response e.g., by immune-cell mediated tissue destruction, has been implicated as the cause of reduced tissue function or loss of tissue function in diseases of the joints (e.g., rheumatoid and osteo-arthritis) and of many organs, including the kidney, pancreas, skin, lung and heart. For example, glomular nephritis, diabetes, inflammatory bowel disease, vascular diseases such as atheroclerosis and vasculitis, and skin diseases such as psoriasis and dermatitis are believed to result in large part from unwanted acute inflammatory reaction and fibrosis. A number of these diseases, including arthritis, psoriasis and inflammatory bowel disease are considered to be chronic inflammatory diseases. The damaged tissue also often is replaced by fibrotic tissue, e.g., scar tissue, which further reduces tissue function. Graft and transplanted organ rejection also is believed to be primarily due to the action of the body's immune/inflammatory response system.
The immune-cell mediated tissue destruction often follows an initial tissue injury or insult. The secondary damage, resulting from the inflammatory response, often is the source of significant tissue damage. Among the factors thought to mediate these damaging effects are those associated with modulating the body's inflammatory response following tissue injury, e.g., cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), and oxygen-derived free radicals such as superoxide anions. These humoral agents are produced by adhering neutrophilic leukocytes or by endothelial cells and have been identified at ischemic sites upon reperfusion. Moreover, TNF concentrations are increased in humans after myocardial infarction.
A variety of lung diseases are characterized by airway inflammation, including chronic bronchitis, emphysema, idiopathic pulmonary fibrosis and asthma. Another type of lung-related inflammation disorders are inflammatory diseases characterized by a generalized, wide-spread, acute inflammatory response such as adult respiratory distress syndrome. Another dysfunction associated with the inflammatory response is that mounted in response to injury caused by hyperoxia, e.g., prolonged exposure to lethally high concentrations of O.sub.2 (95-100% O.sub.2). Similarly, reduced blood flow to a tissue (and, therefore reduced or lack of oxygen to tissues), as described below, also can induce a primary tissue injury that stimulates the inflammatory response.
It is well known that damage occurs to cells in mammals which have been deprived of oxygen. In fact, the interruption of blood flow, whether partial (hypoxia) or complete (ischemia) and the ensuing inflammatory responses may be the most important cause of coagulative necrosis or cell death in human disease. The complications of atherosclerosis, for example, are generally the result of ischemic cell injury in the brain, heart, small intestines, kidneys, and lower extremities. Highly differentiated cells, such as the proximal tubular cells of the kidney, cardiac myocytes, and the neurons of the central nervous system, all depend on aerobic respiration to produce ATP, the energy necessary to carry out their specialized functions. When ischemia limits the oxygen supply and ATP is depleted, the affected cells may become irreversibly injured. The ensuing inflammatory responses to this initial injury provide additional insult to the affected tissue. Examples of such hypoxia or ischemia are the partial or total loss of blood supply to the body as a whole, an organ within the body, or a region within an organ, such as occurs in cardiac arrest, pulmonary embolus, renal artery occlusion, coronary occlusion or occlusive stroke.
The tissue damage associated with ischemia-reperfusion injury is believed to comprise both the initial cell damage induced by the deprivation of oxygen to the cell and its subsequent recirculation, as well as the damage caused by the body's response to this initial damage. It is thought that reperfusion injury may result in dysfunction to the endothelium of the vasculature as well as injury to the surrounding tissue. In idiopathic pulmonary fibrosis, for example, scar tissue accumulates on the lung tissue lining, inhibiting the tissue's elasticity. The tissue damage associated with hyperoxia injury is believed to follow a similar mechanism, where the initial damage is mediated primarily through the presence of toxic oxygen metabolites, followed by an inflammatory response to this initial injury.
Similarly, tissues and organs for transplantation also are subject to the tissue destructive effects associated with the recipient host body's inflammatory response following transplantation. It is currently believed that the initial destructive response is due in large part to reperfusion injury to the transplanted organ after it has been transplanted to the organ recipient.
Accordingly, the success of organ or tissue transplantation depends greatly on the preservation of the tissue activity (e.g., tissue or organ viability) at the harvest of the organ, during storage of the harvested organ, and at transplantation. To date, preservation of organs such as lungs, pancreas, heart and liver remains a significant stumbling block to the successful transplantation of these organs. U.S. Pat. No. 4,952,409 describes a superoxide dismutase-containing liposome to inhibit reperfusion injury. U.S. Pat. No. 5,002,965 describes the use of ginkolides, known platelet activating factor antagonists, to inhibit reperfusion injury. Both of these factors are described as working primarily by inhibiting the release of and/or inhibiting the damaging effects of free oxygen radicals. A number of patents also have issued on the use of immunosuppressants for inhibiting graft rejection. A representative listing includes U.S. Pat. Nos. 5,104,858, 5,008,246 and 5,068,323. A significant problem with many immunosuppressants is their low therapeutic index, requiring the administration of high doses that can have significant toxic side effects.
Rheumatoid and osteoarthritis are prevalent diseases characterized by chronic inflammation of the synovial membrane lining the afflicted joint. A major consequence of chronic inflammatory joint disease (e.g., rheumatoid arthritis) and degenerative arthritis (e.g., osteoarthritis) is loss of function of those affected joints. This loss of function is due primarily to destruction of the major structural components of the joint, cartilage and bone, and subsequent loss of the proper joint anatomy. As a consequence of chronic disease, joint destruction ensues and can lead to irreversible and permanent damage to the joint and loss of function. Current treatment methods for severe cases of rheumatoid arthritis typically include the removal of the synovial membrane, e.g., synovectomy. Surgical synovectomy has many limitations, including the risk of the surgical procedure itself, and the fact that a surgeon often cannot remove all of the diseased membrane. The diseased tissue remaining typically regenerates, causing the same symptoms which the surgery was meant to alleviate.
Psoriasis is a chronic, recurrent, scaling skin disease of unknown etiology characterized by chronic inflammation of the skin. Erythematous eruptions, often in papules or plaques, and usually having a white silvery scale, can affect any part of the skin, but most commonly affect the scalp, elbows, knees and lower back. The disease usually occurs in adults, but children may also be affected. Patients with psoriasis have a much greater incidence of arthritis (psoraitic arthritis), and generalized exfoliation and even death can threaten afflicted individuals.
Current therapeutic regimens include topical or intralesional application of corticosteroids, topical administration of keratolytics, and use of tar and UV light on affected areas. No single therapy is ideal, and it is rare for a patient not to be treated with several alternatives during the relapsing and remitting course of the disease. Whereas systematic treatment can induce prompt resolution of psoriatic lesions, suppression often requires ever-increasing doses, sometimes with toxic side effect, and tapering of therapy may result in rebound phenomena with extensions of lesions, possibly to exfoliation.
Inflammatory bowel disease (IBD) describes a class of clinical disorders of the gastrointestinal mucosa characterized by chronic inflammation and severe ulceration of the mucosa. The two major diseases in this classification are ulcerative colitis and regional enteritis (Crohn's Disease). Like oral mucositis, the diseases classified as IBD are associated with severe mucosal ulceration (frequently penetrating the wall of the bowel and forming strictures and fistulas), severe mucosal and submucosal inflammation and edema, and fibrosis (e.g., scar tissue formation which interferes with the acid protective function of the gastrointestinal lining.) Other forms of IBD include regional ileitis and proctitis. Clinically, patients with fulminant IBD can be severely ill with massive diarrhea, blood loss, dehydration, weight loss and fever. The prognosis of the disease is not good and frequently requires resection of the diseased tissue.
Therefore, an object of the present invention is to provide a method for protecting mammalian tissue, particularly human tissue, from the damage associated with the inflammatory response following a tissue injury. The inflammatory reaction may be in response to an initial tissue injury or insult. The original injury may be chemically, mechanically, immunologically or biologically related. Another object is to provide methods and compositions for protecting tissue from the tissue destructive effects associated with chronic inflammatory diseases, including arthritis (e.g., reheumatoid or osteoarthritis), psoriatic arthritis, psoriasis and dermatitis, inflammatory bowel disease and other autoimmune diseases.
Another object of the invention is to provide methods and compositions for enhancing the viability of mammalian tissues and organs to be transplanted, including protecting the transplanted organs from immune cell-mediated tissue destruction, such as the tissue damage associated with ischemia-reperfusion injury, such as can occur upon initiation of blood flow after transplantation of the organ in the recipient host.
Another object of the invention is to provide a method for alleviating tissue damage associated with ischemic-reperfusion injury in a mammal following a deprivation of oxygen to a tissue in the mammal. Other objects of the present invention include providing a method for alleviating tissue damage associated with ischemic-reperfusion injury in a human which has suffered from hypoxia or ischemia following cardiac arrest, pulmonary embolus, renal artery occlusion, coronary occlusion or occlusive stroke, as well as tissue damage associated with a surgical or other aggressive clinical procedure. Still another object is to provide a method for alleviating tissue damage associated with hyperoxia-induced injury in a human following exposure to lethally high oxygen concentrations.
Still another object of the invention is to provide a method for modulating inflammatory responses in general, particularly those induced in a human following tissue injury.
These and other objects and features of the invention will be apparent from the description, drawings and claims which follow.